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研究生： 康恩宇
Midence Martinez Roberto Andres
論文名稱： 酸敏性離子通道亞型介導的小鼠行為與機械力轉導之探討
On Acid Sensing Ion Channel's Mediation of Subtype-Specific Mechanotransduction and Behavior
指導教授： 陳志成
Chen, Chih-Cheng
共同指導教授: 吳偉立
Wu, Wei-Li
學位類別： 博士
Doctor
系所名稱： 醫學院 - 跨領域神經科學國際博士學位學程
TIGP on The Interdisciplinary Neuroscience
論文出版年： 2022
畢業學年度： 110
語文別： 英文
論文頁數： 91
外文關鍵詞： Neuroscience, Proprioception, ASIC, Mechanotransduction
相關次數： 點閱：102  下載：1 
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    • Proprioception is the integration of somatosensorial information that enables a person to know their body parts’ location, movement, and strains at any given time. Proprioceptive afferent data provides the foundation of our spatial and movement awareness and has been suggested as the foundation for self-awareness. A section of this somatosensorial input comes from an elaborate system of at least 5 types of peripheral nervous system proprioceptors that innervate muscles, joints, and tendons. Unfortunately, molecular and cellular proprioception remain largely unknown because genetic models to study this sensory modality are lacking. The acid-sensing ion (ASIC) family are trimeric membrane channels typically known for their function in sensing tissue acidosis. These, however, have recently emerged as dual-functioned, mechano-sensing ion channels. This role is in line with their phylogeny as a part of the ENaC/DEG family of well-known mechanosensors. Single-cell RNA sequencing studies reveal that ASICs are expressed unevenly in different subtypes of proprioceptors. My hypothesis is that ASIC members play dissimilar and specialized roles in these subtypes, mediating specific modalities of proprioception. These specific roles remain unknown and probing them would provide the genetic tools needed to study proprioceptor subtypes and their specific roles in proprioception.
    Here I present an approach to probe the specific mammalian proprioceptor classes, with the PNS-exclusive ASIC1b at the forefront of the study. The ASICs are modulators of stretch-induced currents in specific subsets of parvalbumin-positive proprioceptors. In situ hybridization reveals the proprioceptor classes that different ASICs modulate, and conditional ASIC knockout mice show specific gait-related phenotypes. Parvalbumin-conditional knockout of ASICs avoid physical contact and tight spaces, hinting at novel roles of proprioceptor subtypes in the modulation of mechanosensory modalities. Additionally, electrophysiological recordings of mechanotransducing properties evidence various roles of ASICs in the modulation of neurite stretch-induced currents, in vitro and ex vivo. Taken together, this thesis presents ASICs as modulators of specific mammalian stretch-induced proprioceptive currents. The modified currents of these proprioceptors result in specific proprioception-related behaviors.

    Table of Contents Acknowledgement ii Abstract vii Figures List viii i. Diagram 1. Collection of relevant anatomical diagrams and references from the literature viii ii. Diagram 2. Current and planned genetic strategies viii iii. Diagram 3. Working model for ASIC1b influence in proprioceptive-related behavior viii iv. Figures viii a. Figure 1. Three major Pv+ proprioceptor groups in the L4 dorsal root ganglia reveal their RNA in situ hybridization patterns with ASIC1b viii b. Figure 2. Three major Pv+ proprioceptor groups in the L4 dorsal root ganglia reveal their RNA in situ hybridization patterns with ASIC3 viii c. Figure 3. Colocalization patterns of ASIC1b and ASIC3 viii d. Figure 4. T Three major Pv+ proprioceptor groups in the L4 dorsal root ganglia reveal their RNA in situ hybridization patterns pertaining ASIC1b and ASIC3 viii e. Figure 5. Spatiotemporal gait analysis of different Pv and Nav1.8 conditional KOs of ASICs viii f. Figure 6. Standard deviations in gait analysis parameters of different Pv and Nav1.8 conditional KOs of ASICS viii g. Figure 7. Balance beam walking task viii h. Figure 8. Grid walking task viii i. Figure 9. Locomotion and physiology-related parameters viii j. Figure 10. Tube Social Dominance viii k. Figure 11. Pre-Pulse Inhibition viii l. Figure 12. Elevated Plus Maze viii m. Figure 13. Three-Chamber Social Preference viii n. Figure 14. Juvenile Play viii o. Figure 15. Digging behavior of phenotyped mice viii p. Figure 16. Thigmotaxis analysis in bright conditions ix q. Figure 17. Thigmotaxis analysis in dark conditions ix r. Figure 18. Thigmotaxis analysis under whiskerless conditions ix s. Figure 19. Substrate indentation deformation-driven electrophysiology experiment DRG neuronal primary culture setup ix t. Figure 20. General parameters of parvalbumin muscle afferents in substrate-indentation driven electrophysiological current experiments ix u. Figure 21. Multiple variable analysis of DRG muscle afferent neuronal populations ix v. Figure 22. ASICs effect on substrate-indentation driven currents of group alpha Pv+ muscle afferent neurons ix w. Figure 23. ASICs effect on substrate-indentation driven currents of group beta Pv+ muscle afferent neurons ix x. Figure 24. Genetic strategies for AA viruses ix y. Figure 25. AAV-driven conditional expression of WGA for retrograde labeling of muscle afferent Pv+ neurons ix z. Figure 26. Immunohistology imaging of the dorsal column nuclei ix aa. Figure 27. c-Fos staining of the dorsal column nuclei ix bb. Figure 28. pERK staining of the dorsal column nuclei nuclei ix cc. Figure 29. Proof-of-concept experimental approaches to probing the dorsal column nuclei ix Abbreviations x Chapter 1. Introduction 1 Proprioception 1 The Proprioceptor Classes 2 Molecular Tools 3 The Acid Sensing Ion Channels 3 ASIC Subtypes/Subunits and Their Trimeric Nature 4 The Dorsal Column Nuclei (DCN) 5 Connections Between the CNS and PNS 5 The Ascending Tracts 6 The Dorsal Column Nuclei Complex (DCN) 7 Sensorial Distribution in the Medulla 9 Significance 11 The Central Hypothesis and Purpose of This Thesis 12 Chapter 2. Materials and Methods 13 In-situ RNA Hybridization 13 Mouse Behavior Experiments 14 Spatiotemporal Analysis of Gait Patterns 15 Grid Walking Test 16 Balance Beam 16 Rotarod 17 Dominance Tube 17 Juvenile Play 18 Open-Field and Edge Preference Analysis 19 Three-Chamber Social Preference 19 Elevated Plus Maze 20 Marble Burying 20 Pre-Pulse Inhibition (Startle Response) 21 Substrate-Deformation Driven Stretch Electrophysiology Recordings 21 Multiple Variable Data Analysis 25 AAV Virus Retrograde Tracing 26 Chemo-optogenetic Channel Activation 27 Statistical Analysis 30 Chapter 3. ASIC Colocalization with Proprioceptors 31 Introduction 31 Results 31 Discussion 32 Chapter 4. ASIC Subtype Specific Behavioral Phenotypes 33 Introduction 33 Results 34 Discussion 35 Chapter 5. ASICS in Substrate-Stretch Driven Currents 38 Introduction 38 Results 40 Discussion 41 Chapter 6. Techniques to Target the Central Nervous System 43 Introduction 43 Results 43 Discussion 44 Chapter 7. Chemo-optogenetics 45 Introduction 45 Results 46 Discussion 47 Chapter 8. An Experimental Model for ASIC1b Somatosensorial Modulation 48 References 51 Anatomical References and Diagrams 59 Genetic Strategies 60 Working Model 62 Figures 63

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